COMPOUNDS FOR INDUCING PROLIFERATION AND DIFFERENTIATION OF CELLS, AND METHODS OF USE THEREOF

• US 20160031837A1
• Filed: 03/14/2014
• Published: 02/04/2016
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology, The Broad Institute, Inc.
• Original Assignee: Massachusetts Institute of Technology, The Broad Institute, Inc.
• Inventors: Bhatia, Sangeeta, Shan, Jing, Palmer, Michelle, Ross, Nathan
• Granted Patent: US 10,081,609 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/0331 Animal model for proliferative diseases
• CPC Class Codes: A01K 67/0278 Knock-in vertebrates, e.g. humanised vertebrates
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• CPC Class Codes: A61K 31/4174 Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
• CPC Class Codes: A61K 31/4409 only substituted in position 4, e.g. isoniazid, iproniazid
• CPC Class Codes: A61K 35/12 Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells vaccines or medicinal preparations containing antigens or antibodies A61K39/00
• CPC Class Codes: A61K 35/407 Liver; Hepatocytes
• CPC Class Codes: C07C 211/32 containing dibenzocycloheptane or dibenzocycloheptene ring systems or condensed derivatives thereof
• CPC Class Codes: C07D 209/48 with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 209/88 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 263/24 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
• CPC Class Codes: C12N 2501/02 Compounds of the arachidonic acid pathway, e.g. prostaglandins, leukotrienes
• CPC Class Codes: C12N 2501/115 Basic fibroblast growth factor (bFGF, FGF-2)
• CPC Class Codes: C12N 2501/12 Hepatocyte growth factor [HGF]
• CPC Class Codes: C12N 2501/155 Bone morphogenic proteins [BMP]; Osteogenins; Osteogenic factor; Bone inducing factor
• CPC Class Codes: C12N 2501/16 Activin; Inhibin; Mullerian inhibiting substance
• CPC Class Codes: C12N 2501/237 : Oncostatin M [OSM]
• CPC Class Codes: C12N 2501/999 : Small molecules not provided for elsewhere
• CPC Class Codes: C12N 2503/02 : Drug screening
• CPC Class Codes: C12N 2506/45 : from artificially induced pluripotent stem cells
• CPC Class Codes: C12N 2533/90 : Substrates of biological origin, e.g. extracellular matrix, decellularised tissue
• CPC Class Codes: C12N 5/06 : Animal cells or tissues; Human cells or tissues preservation of living cells or tissues A01N1/02
• CPC Class Codes: C12N 5/067 : Hepatocytes
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention provides methods of inducing proliferation of and/or differentiating cells comprising contacting cells with compounds within the methods of the invention. The present invention further provides cells obtainable by the methods of the invention. Liver disease affects more than 500 million people worldwide. Organ transplantation is the gold standard for treatment of liver failure, but organ shortages are acute.

Claims

1. A method of inducing proliferation of one or more primary cells, the method comprising contacting the one or more primary cells with a compound selected from the group consisting of:

Compound 109 (PH1, or 4-(3-butoxy-4-methoxybenzyl)imidazolidin-2-one);

Compound 110 ((1R,4R)-4-((R)-1-aminoethyl)-N-(pyridin-4-yl)cyclohexane-1-carboxamide);

Compound 111 ((1R,4R)-4-((R)-1-aminoethyl)-N-(pyridin-4-yl)cyclohexane carboxamide);

Compound 112 (1-((9H-carbazol-4-yl)oxy)-3-((2-(2-methoxyphenoxy)ethyl)amino) propan-2-ol);

Compound 113 (3-(5H-dibenzo[a,d][7]annulen-5-ylidene)-N,N-dimethylpropan-1-amine);

Compound 114 (2-(2-(1,3-dioxoisoindolin-2-yl)acetamido)acetic acid);

a compound of Formula (I);

2. The method of claim 1, wherein the at least one compound is selected from the group consisting of:

3. The method of claim 1, wherein the one or more primary cells comprise one or more somatic cells that are obtained from a subject or are part of a subject'"'"'s body, that comprise one or more adult cells;

comprise one or more epithelial cells or endothelial cells;

comprise one or more hepatocytes;

comprise one or more stem cells;

comprise a pluripotent or non-pluripotent cell.

14. One or more cells produced by the method of claim 1.

21. A method of treating, alleviating or preventing a disease or condition in a subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of at least one agent selected from the group consisting of:

(i) at least one compound selected from the group consisting of Compounds 109-114, a compound of Formula (I)-(V), enantiomers or diastereoisomers thereof, prodrugs thereof, pharmaceutically acceptable salts thereof and any combinations thereof;

(ii) one or more cells obtained by the method of claim 1 or claim 14.

22. The method of claim 21, wherein the at least one compound in (i) induces functional proliferation of endogenous cells or promotes differentiation of endogenous cells.

27. The method of claim 21, wherein the liver disease is selected from acetaminophen toxicity, alcoholic liver disease, primary liver cancer, liver cirrhosis, liver cysts, fatty liver disease, liver fibrosis, hepatitis, primary sclerosing cholangitis, jaundice, and any combinations thereof.

28. The method of claim 21, wherein administration of the one or more cells in (ii)-(iii) to the subject comprises implanting in the subject a bio-artificial liver device comprising the one or more cells.

29. The method of claim 28, wherein the subject is further administered an effective amount of at least one compound selected from the group consisting of Compounds 109-114, a compound of Formula (I)-(V), enantiomers or diastereoisomers thereof, prodrugs thereof, pharmaceutically acceptable salts thereof and any combinations thereof.

30. The method of claim 27, wherein the hepatitis is caused by a virus selected from the group consisting of hepatitis A-E virus, herpes simplex, cytomegalovirus, Epstein-Barr virus, yellow fever, and any combinations thereof.

33. A method of performing tissue or organ transplant in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one agent selected from the group consisting of:

(i) at least one compound selected from the group consisting of Compounds 109-114, a compound of Formula (I)-(V), enantiomers or diastereoisomers thereof, prodrugs thereof, pharmaceutically acceptable salts thereof and any combinations thereof;

(ii) one or more cells obtained by the method of claim 1 or claim 14.

34. The method of claim 33, wherein the organ comprises liver.

35. A method of repairing damaged, diseased or aged tissue in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one agent selected from the group consisting of:

(i) at least one compound selected from the group consisting of Compounds 109-114, a compound of Formula (I)-(V), enantiomers or diastereoisomers thereof, prodrugs thereof, pharmaceutically acceptable salts thereof and any combinations thereof;

(ii) one or more cells obtained by the method of claim 1 or claim 14.

36. The method of claim 35, wherein the tissue comprises liver tissue.

40. A method of developing a humanized mouse model, the method comprising administering to a mouse at least one cell selected from the group consisting of (i) one or more cells obtained by methods of claim 1;

(ii) one or more cells of claim 14; and

any combinations thereof.

4-13. -13. (canceled)

15. A method of inducing differentiation of one or more induced pluripotent stem cells (iPS cell), the method comprising contacting the one or more iPS cells with at least one compound selected from the group consisting of Compounds 109-114, a compound of Formula (I)-(V), enantiomers or diastereoisomers thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, and any combinations thereof, whereby contacting the one or more iPS cells with the at least one compound induces differentiation of the one or more iPS cells.

16. The method of claim 15, wherein the at least one compound is selected from the group consisting of Compounds 101-114, 201-212, 215, 217, 224-257, enantiomers or diastereoisomers thereof, prodrugs thereof, pharmaceutically acceptable salts thereof and any combinations thereof.

20. One or more cells produced by the method of claim 15.

17-19. -19. (canceled)

23-26. -26. (canceled)

31-32. -32. (canceled)

37. A method of providing cell replacement therapy to a subject in need thereof, the method comprising:

(i) contacting one or more cells with at least one compound selected from the group consisting of Compounds 109-114, a compound of Formula (I)-(V), enantiomers or diastereoisomers thereof, prodrugs thereof, pharmaceutically acceptable salts thereof and any combinations thereof, thereby generating one or more differentiated cells; and

(ii) administering the one or more differentiated cells to the subject.

38-39. -39. (canceled)

41. (canceled)